Developing Optogenetic Approaches to Study Ca²⁺ Signaling Processes

Calcium ions (Ca²⁺) are essential second messengers intimately implicated in a variety of biological processes, ranging from short-term events such as muscle contraction to long-term effects like gene expression. Dysregulated Ca²⁺ signaling can disrupt cellular function and contribute to the development of various human diseases, including developmental, neurological, immunoinflammatory, metabolic, and cardiovascular disorders. To study the mechanisms and biological consequences of Ca²⁺ signaling, optogenetic approaches have proven invaluable, as they offer exceptional spatiotemporal resolution compared to traditional methods. Recent progress in non-opsin-based optogenetics, particularly those engineered from Ca²⁺ release-activated Ca²⁺ (CRAC) channels, has substantially advanced our understanding of Ca²⁺ signaling mechanisms. These tools have enabled precise manipulation of downstream signaling events, opening new avenues for therapeutic interventions. In this review, we examine the principles behind the design and engineering of light-sensitive calcium actuators and modulators (designated LiCAMs) and the applications of representative LiCAMs in remote and noninvasive control of Ca²⁺-modulated physiological processes both in vitro and in vivo.